This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent moiety is a cyclobutenedione-substituted indol-3-yl-alkyl group and the other moiety is a pyridinyl or pyrimidinyl ring. These compounds possess a unique serotonergic profile that renders them useful in treatment of vascular headaches such as migraine or cluster type.
Archer disclosed a large series of CNS-depressant indolylalkylpiperazines in U.S. Pat. No. 3,188,313. Among a large number of possible substituents on the 4-nitrogen atom of the piperazine ring was pyrimidine. In U.S. Pat. No. 3,562,278, Archer disclosed and claimed a series of 1-indolylethyl-4-substituted-piperazines. Among the possible 4-substituents listed is 2-pyrimidinyl. The pharmacologic action disclosed for these art compounds is general CNS and psychomotor depression which bear no relationship to an antimigraine therapeutic agent.
Dowie, et al. disclosed a series of 3-alkylaminoindole derivatives as being potentially useful for the treatment of migraine in a published patent application, GB 2,124,210. One member of this series of compounds was specifically claimed in a later patent application of Oxford, GB 2,162,522, published Feb. 5, 1986. This particular compound is known in the literature as sumatriptan(i). ##STR2##
A series of novel indoline derivatives were disclosed Feb. 7, 1990 by Manoury, et al., in European patent application EPA 354,094. These compounds are described as being useful for treatment of various CNS disorders including depression, anxiety and migraine. Included among these art compounds are those of formula (ii) ##STR3## wherein R.sup.4 is aryl, pyridine or quinoline moieties.
Smith, et al. in U.S. Pat No. 4,954,502 have disclosed a series of 1,4-disubstituted piperazine derivatives of formula (iii) which are useful as antidepressant agents. ##STR4##
The indolyl substituents R.sup.3 and R.sup.4 were hydrogen, alkyl, alkoxy, alkylthio, halogen, carboxamide, and trifluoromethyl.
Another series of antidepressant 1,4-disubstituted piperazines where pyrimidine moieties were used instead of pyridine was set forth by Smith, et al. in U.S. Pat. No. 5,077,293.
The most relevant background is believed to be our earlier work which disclosed antimigraine alkoxypyrimidine derivatives of formula (iv) ##STR5## wherein the indole substituents (R.sup.1 and R.sup.6) were halogen, hydroxy, alkoxy and sulfonamido.
None of these art compounds suggest the instant novel 5-cyclobutenedione-substituted-indol-3-ylalkyl derivatives of pyridinyl or pyrimidinylpiperazines for the treatment of migraine and cluster-type headaches.
Migraine is a member of a broader class of headache that also comprises cluster headaches and other headaches believed to have a vascular implication in their etiology. These headaches are often classified as vascular headaches. For a current summary of headache and its treatment see: Chapter 13: "Drugs Used to Treat Migraine and Other Headaches" in Drug Evaluations, 6th Edn., 1986, pages 239-253 American Medical Association, W. B. Saunders Co., Philadelphia, Pa.
Frequent irregularly-occurring episodes of headache afflict a large number of people but are usually acute in nature and of short duration. Relief of this type of headache is typically provided by mild analgesics such as aspirin or acetaminophen. Such headaches are quite common and, while painful and perhaps annoying, are seldom incapacitating and debilitating. Chronic recurrent headaches of the vascular category, however, usually lead to patient consultation with a physician due to pain severity which is often incapacitating.
Although there is no universally accepted classification system for headache, vascular headache, for the purposes of the present invention, refers mainly to migraine and cluster headaches. Migraine includes the common or classical type as well as migraine variants which would be familiar to one skilled in the art. Other subtypes such as toxic vascular and hypertensive headaches, chronic paroxysmal hemicrania, as well as some muscle-contraction and combined or mixed vascular-muscle headaches may also fall into a vascular-related headache category and be treatable by the present invention. It is appreciated by one skilled in the art that no single therapy is effective in all patients diagnosed with the same subtype of headache, thereby raising further uncertainties about headache classification.
Drugs most commonly used in treatment of headache fall into the following groups:
Ergot Alkaloids, PA1 Beta-blocking Agents, PA1 Calcium Channel Blocking Agents, PA1 Antidepressants, and PA1 Mixtures of these. PA1 R.sup.2 and R.sup.3 are independently selected from hydrogen and lower alkyl. In preferred compounds R.sup.2 and R.sup.3 are usually not lower alkyl at the same time. PA1 R.sup.4 can be hydrogen or lower alkoxy. PA1 W can be either a single covalent carbon-carbon bond or --NR.sup.5 --, where R.sup.5 is selected from hydrogen, lower alkyl, lower acyl, and lower alkylsulfonyl. PA1 X is selected from --NR.sup.2 R.sup.3; --OR.sup.2 ; and R.sup.6, with R.sup.6 being hydrogen, lower alkyl, cycloalkyl, aryl, or aryl-lower alkyl. PA1 Y and Z are independently selected from N and CH with the proviso that both Y and Z cannot be CH simultaneously.
Management of recurring vascular headache is complicated by the lack of a single therapy which is effective in all patients with the same headache type and by the need to select either an abortive or prophylactic method of treatment for these headaches. Further complication involves the current use of drugs that cause dependence with extended use, such as ergotamine. Another important consideration for the present invention is that the more effective antimigraine agents in current use, e.g. the ergots, and methysergide, produce severe use-limiting side-effects with long term usage.
Thus there is a need for a safe and effective drug for the treatment of migraine and related disorders which can be used either prophylactically or to alleviate an established headache.
The objectives of the present invention relate to the use of novel cyclobutenedione-substituted-indol-3-ylalkyl derivatives of pyridinyl- and pyrimidinylpiperazines to provide treatment of vascular headaches, particularly migraine and cluster-types; to processes for their preparation; and to their pharmaceutical compositions and medical usage.